PROCESS FOR PREPARATION OF SOLID DISPERIONS AND DEPOSITS AS WELL AS OF SOLID MEDICINAL FORMS WITH DIHYDROPYRIDINE TYPE CALCIUM ANTAGONISTS

Abstract: There is described a process for the preparation of solid dispersions and deposits with dihydropyridine type calcium antagonists containing as the active substance one or more 1,4-dihydropyridine derivatives such as nitrendipine, nimodipine and lacidipine and as a carrier one or more water-soluble derivatives of mono-, di-, oligo- and polysaccharides, and, if required, also polymer substances, which are swellable in contact with water, selected from polacrilin potassium, sodium starch glycolate and/or cross-linked carboxy methyl cellulose, and anionogenic or non-ionogenic type surfactants selected from sodium lauryl sulfate, poloxamers and/or higher fatty acids polyoxyethylene sorbitan esters, whereat from the dispersion, preferably a solution and/or suspension of active substance(s), and if required one or more water-soluble adjuvants, selected from mono, di and oligosaccharides, and surfactants selected from sodium lauryl sulfate, poloxamers and/or polyoxyethylene sorbitan esters of higher fatty acids with 12 to 18 carbon atoms, in a solvent selected from lower aliphatic alcohols with 1 to 4 carbon atoms, preferably ethanol and 1-propanol and if required in mixture with water, the solvent is removed by spraying of dispersion under the stream of the heat air and if required to the carrier, selected from one or more of the water-soluble mono, di, oligo and polysaccharides and if required the water-swellable polymer substances from the group of disintegrators, and the anionic or nonionic surfactants. Furthermore, there is described a process for the preparation of solid medicinal forms of dihydropyridine type calcium antagonists, whereat the mentioned solid dispersions and (or) deposits are mixed in a suitable manner with disintegrators and lubricant, and if required the other adjuvants such as carriers and binders, and then by such a mixture there are formed preferably tablets and capsules.

Description: PROCESS FOR PREPARAΗON OF SOLID DISPERSIONS AND DEPOSITS AS WELL AS OF SOLD3 MEDICINAL FORMS WITH DD3YDROPYRTOINE TYPE CALCIUM ANTAGONISTS Technical Field The present invention relates to the process for the preparation of solid dispersions and deposits as well as of solid medicinal forms with dihydropyridine type calcium antagonists. Technical Problem A too low dissolution rate of medicinal active substances from solid medicinal preparations may lead to an incomplete absorption and to a too low biological availability thereof. Due to the regulative requirements, the most suitable solution in connection with the too slow dissolution rate is represented by the pharmaceutical-technological ap¬ proach being realized in the simplest way by micronization. However, at strongly aerophilic active substances, to which also 1,4-dihydropyridine derivatives with an¬ tagonistic action upon the receptors within calcium channels belong, micronization does not always result in an increase of the dissolution rate. Therefore at developing formulations including one or more 1,4-dihydropyridine derivatives characterized by very bad solubility and low dissolution rate in water, this approach could not be used. FriorArt It is known that the dissolution rate of a medicinal active substance is directly in¬ fluenced by the surface of the dissolving particles and the solubility of the active sub¬ stance. In the patent literature there are described technological solutions of increas¬ ing the dissolution rate by micronization. In DE 3310649 and EP 142561 by BAYER AG, the particle size of micronized dihydropyridine type calcium antagonists is protected. The dissolution rate is also increased by the preparation of solid dispersions of the active substance with an appropriate hydrophilic, biologically non-active compound, e.g. coloidal silicon dioxide, PVP, sugars, etc. Among the mentioned dispersions, there are of special importance the so-called solid surface dispersions (adsorbates and deposits), whose theoretical and practical basis was developed by Rupprecht et al, especially for the use of carriers on the basis of silicon dioxide (natural and artifi¬ cially obtained). The preparation of such dispersions on an industrial scale is often difficult or not feasible at all (YU patent 44 291), as it often includes the phase of evaporating greater amounts of organic solvents and the use of voluminous carriers, which are not suitable for the preparation of solid forms with active substances, whose dose is higher than 10 mg. On the other hand, the physical state of the active substance in such dispersions is unstable. By mechanical treatment it is often changed, which is reflected in a lower dissolution rate. In DE 3419128 there is described a process for the preparation of a formulation with 1,4-dihydropyridine derivatives, wherefrom the active substance is released rapidly and reliably. The cited application protects a classical process of granulation of the active substance selected from 1,4-dihydropyridine derivatives with water-soluble ex- cipients such as lactose, saccharose, fructose, glucose, mannitol, sorbitol, some alkaline and alkaline earth salts of organic acids and other excipients such as starch, cellulose, PVP and colloidal silicon dioxide. The Inventive Solution The present invention includes technological processes and methods, which make possible the preparation of solid dispersions and/or deposits of one or more 1,4- dihydropyridine derivatives with appropriate pharmacologically indifferent com¬ pounds selected from mono-, di-, oligo- and polysaccharides and the preparation of solid medicinal forms with incorporated dispersions and/or deposits. At the prepara¬ tion of the said solid dipersions and deposits methods are used, whereat a dispersion (solution or suspension) composed of one or more 1,4-dihydropyridine derivatives and of an appropriate carrier selected from mono-, di-, oligo- and polysaccharides, colloidal silicon dioxide or microciystalline cellulose is sprayed according to one of the following methods: - spraying in a spray dryer or - spraying in a fluid bed. In other words, solid compositions in connection with this application are preferably: 1. solid dispersions, where the drug (one or more 1,4-dihydropyridines) is homogeneously dispersed in the matrix of pharmacologically inactive sub¬ stances which comprise one or more water-soluble mono, di, oligo and/or polysaccharides, surfactants and one or more disintegrators; 2. solvent deposits where the drug is loaded, optionally together with the surfac¬ tant, onto the surface of the carrier(s) selected from one or more mono, di, oligo or poylsaccharides, preferably in the mixture with one or more disin¬ tegrators, or 3 a combination of both solid dispersion and solvent deposit, where the drug is loaded in the form of solid dispersion with water soluble mono, di, oligo and polysaccharides and surfactants onto the surface of the carrier selected from one or more mono, di, oligo and polysaccharides, preferably in the mixture with one or more disintegrators. Solid compositions described above can be, according to our invention, produced by: — spraying all the ingredients dispersed into the alcohols, preferably in the mix¬ ture with water, in a spray dryer, — spraying a suspension or solution of a mixture of one or more 1,4- dihydropyridines, at least one surfactant and one or more water soluble mono, di, oligo or polysaccharides in alcohol, preferably in the mixture with water, onto the hydrophilic carrier, which is composed of one or more mono, di, oligo and/or polysaccharides, preferably in the mixture with one or more dis¬ integrators in a fluid bed equipment or — evaporating the solvent from the dispersion of all ingredients in the alcohol, preferably in the mixture with water, under reduced pressure. From the solid compositions prepared in such a manner and containing a total of 1 to 75% (preferably 2.5 to 25%) of 1,4-dihydropyridine derivatives with antagonistic ac¬ tion upon the receptors at calcium channels, by the addition of a superdisintegrator selected from sodium starch glycolate, polacrilin potassium, cross-linked carboxy methyl cellulose and cross-linked PVP and of anionic and/or non-ionic surfactants and other known adjuvants, there are formed solid medicinal forms such as capsules, tablets (classic or coated) or dragees. The object of the present invention is thus a process for preparing solid compositions containing 1,4-dihydropyridine derivatives, which comprises: (a) preparing a solution or suspension of one or more 1,4-dihydropyridines, one or more water soluble mono, di, oligo or polysaccharides and preferably one or more surfactants in a hydrophilic solvent, (b) providing at least one carrier selected from mono, di, oligo and poly¬ saccharides, the carrier being preferably mixed with one or more disin¬ tegrators, (c) evaporating the solvent by spraying the solution or suspension (a) onto the carrier (b) under a stream of heated air. A further object of the present invention is a process for preparing solid composi¬ tions containing 1,4-dihydropyridine derivatives, which comprises: (i) preparing a solution or suspension of one or more 1,4-dihydropyridines, one or more water soluble mono, di, oligo or polysaccharides in a hydrophilic sol¬ vent, the solution or suspension preferably including one or more surfactants and/or one or more disintegrators, and (ii) evaporating the solvent. The surfactant is selected from sodium lauryl sulphate, substitued and unsubstituted polyoxyethylene-polyoxypropylene blockpolymers and polyoxyethylene sorbitan esters of higher fatty acids with 10-18 carbon atoms per molecule and preferably from sodium lauryl sulphate, α-hydro-o-hydroxypoly(oxyethylene) a -poly(oxy- propylene) b -poly(oxyethylene) a blockpolymer, where a is 80 or 101 and b is 27 or 56, and polyoxyethylene sorbitan monooleate. Soluble starch, lactose, mannitol, sorbitol and/or glucose, preferably sorbital, man- nitol and/or lactose are used as the water soluble saccharide in step (a) and step (i) and as saccharide in step (b). The disintegrator is selected from methacrylic acid-divinyl-benzene copolymer potas¬ sium salt (polacrilin potassium), sodium starch glycolate and cross-linked carboxy methyl cellulose and preferably from sodium starch glycolate and cross-linked car¬ boxy methyl cellulose. E.g. nitrendipine, nimodipine and/or lacidipine are used as 1,4-dihydropyridine derivatives. Lower aliphatic alcohols having one to four carbon atoms and containing 0 to 50% by volume of water are used as the hydrophilic solvent. The lower aliphatic alcohols are preferably ethanol and/or 1-propanol. A fluid bed process is used in step (c). The solvent is removed by using spray drying or by drying under reduced pressure and elevated temperature. The technological processes and the used ingredients of the present invention provide a comparable or an even faster release of the active substance from solid medicinal forms than in the case of the formulation according to DE 3419128, whereat at the same time the mentioned processes also dispose of the need for the micronization of the medicinal active substance and of the problems connected therwith. This ensures a lower energy consumption, a smaller loss of the active sub¬ stance and a greater homogeneity of the final solid medicinal form. The present invention also includes the preparation of solid medicinal forms such as capsules, tablets (classic or coated) or dragees containing at least one of the following 1,4-dihydropyridine derivatives: nitrendipine, nimodipine and lacidipine in an amount of 2 to 240 mg per dose and provides for a stable and rapid release of the ac¬ tive substance from the formulation. In addition to one or more said active sub¬ stances, this invention also includes one or more adjuvants selected from water- soluble carriers selected from mono-, di-, oligo- and polysaccharides, preferably sor- bitol, lactose, water-soluble starch and mannitol in concentrations of 5-90%; one or more substances from the group of disintegrators, preferably sodium starch glycolate, polacrilin potassium, cross-linked sodium carboxy methyl cellulose and/or cross- linked polyvinylpyrrolidone in a concentration of 5 to 20%; one or more anionic or non-ionic surfactants selected from the esters and ethers of sorbitan, polyethylene glycol and polypropylene glycol, poloxamers, alkylsulfonic acid alkali salts in a con¬ centration of 0.05 to 10% and other commonly known adjuvants selected from the groups of binders, preferably microciystalline cellulose, and lubricants, preferably magnesium or aluminium stearate. The advantages of the preparation of the solid medicinal forms with dihydropyridine type calcium antagonists according to the process of the present invention in com¬ parison to the other patented or commercial processes comprise, in addition to the better pharmacokinetic characteristics of formulation, also the use of practically non- toxic solvents and the rapidity and efficiency of the process. EXAMPLES I) Dispersions/deposits oExample 1 nitrendipine 100.0 g mannitol 900.0 g ethanol (96% by vol.) q.s. Nitrendipine was dissolved in ethanol and then mannitol was dispersed into the solu¬ tion. The solvent was removed from the dispersion by spraying under a stream of heated air. The final product was sieved through the sieve with 200μm openings. oExample 2 nitrendipine 100.0 g lactose 900.0 g mixture ethanol (96% by vol.)/water 2+1 q.s. Nitrendipine and lactose were dissolved in a mixture of ethanolAvater and then it was proceeded according to the same process as in example 1. oExample 3 nitrendipine 250.0 g lactose 750.0 g mixture ethanol (96% by vol.)/water 2+1 q.s. The process for the preparation of a dispersion was the same as in example 2. Example 4 nimodipine 100.0 g lactose 890.0 g sodium lauryl sulfate 10.0 g mixture ethanol (96% by vol.)/water q.s. Preparation process: a) All solid components were dissolved in a mixture of solvents, which were removed according to the same process as in example 2. b) One or more 1,4-dihydropyridine derivatives and sodium lauryl sulfate were dissolved in a mixture of solvents. The solution was then sprayed under a stream of heated air to the lactose. The obtained dispersion was sieved through a 200μm sieve. Example 5 nitrendipine 10.0 g lactose 120.0 g corn starch 128.0 g microcrystalline cellulose 43.0 g calcium carbonate 35.0 g sodium lauryl sulfate 1.0 g The above listed ingredients were mixed in a planetary mixer and granulated with a PVP water solution. The granulate was dried until a 4.5% moisture was reached. ID Preparation of solid medicinal forms Example 6 The granulate of the example 5 with the addition of 5.0 g magnesium stearate was pressed into tablets. Example 7: nitrendipine 20 mg tablets dispersion of example 2 200.0 g sodium lauryl sulfate 10.0 g PVP CL 14.0 g microciystalline cellulose 24.0 g aluminium stearate 2.0 g Process: The components were mixed homogeneously and directly tableted. Example 8: nimodipine 30 mg tablets dispersion according to 4b 300.0 g sodium starch glycolate 35.0 g microciystalline cellulose 62.0 g magnesium stearate 3.0 g The process was the same as in Example 7. In the enclosed Figs. 1 to 3, Fig. shows a comparison of the dissolution profiles of dis¬ persions of examples 2 and 5 vs. the dissolution profile of micronized nitrendipine, Fig. 2 shows a comparison of the thermograms of the dispersion of Example 2 vs. the granulate of Example 5, and Fig. 3 shows a comparison of the dissolution profiles of 20 mg nitrendipine tablets of Examples 6 and 7.

Claims: CLAIMS 1. Process for preparing solid compositions containing 1,4-dihydropyridine derivatives, which comprises: (a) preparing a solution or suspension of one or more 1,4-dihydro- pyridines, one or more water soluble mono, di, oligo or polysac¬ charides and preferably one or more surfactants in a hydrophilic sol¬ vent, (b) providing at least one carrier selected from mono, di, oligo and poly¬ saccharides, the carrier being preferably mixed with one or more disin¬ tegrators, (c) evaporating the solvent by spraying the solution or suspension (a) onto the carrier (b) under a stream of heated air. 2. Process for preparing solid compositions containing 1,4-dihydropyridine derivatives, which comprises: (i) preparing a solution or suspension of one or more 1,4-dihydro- pyridines, one or more water soluble mono, di, oligo or polysac¬ charides in a hydrophilic solvent, the solution or suspension preferably including one or more surfactants and/or one or more disintegrators, and (ii) evaporating the solvent. 3. Process according to claim 1 or 2, wherein the surfactant is selected from sodium lauryl sulphate, substitued and unsubstituted polyoxyethylene- polyoxypropylene blockpolymers and polyoxyethylene sorbitan esters of higher fatty acids with 10-18 carbon atoms per molecule and preferably from sodium lauryl sulphate, α-hydro-o-hydroxypoly(oxyethylene) -poly(oxy- propylene) b -poly(oxyethylene) a blockpolymer, where a is 80 or 101 and b is 27 or 56, and polyoxyethylene sorbitan monooleate. 4. Process according to any one of the claims 1 to 3, wherein soluble starch, lac¬ tose, mannitol, sorbitol and/or glucose, preferably sorbital, mannitol and/or lactose are used as the water soluble saccharide in step (a) and step (i) and as saccharide in step (b). 5. Process according to any one of the claims 1 to 4, wherein the disintegrator is selected from methacrylic acid-divinyl-benzene copolymer potassium salt (polacrilin potassium), sodium starch glycolate and cross-linked carboxy methyl cellulose and preferably from sodium starch glycolate and cross-linked carboxy methyl cellulose. 6. Process according to any one of the claims 1 to 5, wherein nitrendipine, nimodipine and/or lacidipine are used as 1,4-dihydropyridine derivatives. 7. Process according to any one of the claims 1 to 6, wherein lower aliphatic al¬ cohols having one to four carbon atoms and containing 0 to 50% by volume of water are used as the hydrophilic solvent. 8. Process according to claim 7, wherein the lower aliphatic alcohols are ethanol and/or 1-propanol. 9. Process according to claim 1, wherein a fluid bed process is used in step (c). 10. Process according to claim 2, wherein the solvent is removed by using spray drying or by drying under reduced pressure and elevated temperature.

Inventors: FILIPCIC-MOCNIK MARIJA, GUSTIN JOZICA, VRECER FRANC, FILIPCIC-MOCNIK, MARIJA, GUSTIN, JOZICA, VRECER, FRANC
Applicants: FILIPCIC MOCNIK MARIJA, GUSTIN JOZICA, KRKA TOVARNA ZDRAVIL, VRECER FRANC, FILIPCIC-MOCNIK, MARIJA, GUSTIN, JOZICA, KRKA TOVARNA ZDRAVIL, P.O., VRECER, FRANC
Application year: 1994
Main classification: A61K9
IPC codes: A61K9, A61K31, C07D401